A randomized controlled study to assess the effect of mosapride citrate on intestinal recovery following gastrectomy

The enhanced recovery after surgery (ERAS) protocol, including prokinetic medications, is commonly used to prevent postoperative ileus. Prospective studies evaluating the effectiveness of mosapride citrate, a prokinetic 5-hydroxytryptamine 4 receptor agonist, in patients undergoing gastrectomy within the ERAS framework are lacking. This double-blind randomized trial included patients who were scheduled for laparoscopic or robotic gastrectomy for gastric cancer. Participants were randomly assigned to either a control (placebo) or experimental (mosapride citrate) group, with drugs administered on postoperative days 1–5. Bowel motility was evaluated based on bowel transit time measured using radiopaque markers, first-flatus time, and amount of food intake. No significant differences were observed in baseline characteristics between the two groups. On postoperative day 3, no significant difference was observed in the number of radiopaque markers visible in the colon between the groups. All factors associated with bowel recovery, including the time of first flatus, length of hospital stay, amount of food intake, and severity of abdominal discomfort, were similar between the two groups. Mosapride citrate does not benefit the recovery of intestinal motility after minimally invasive gastrectomy in patients with gastric cancer. Therefore, routine postoperative use of mosapride citrate is not recommended in such patients.


Patient selection
Patients aged 20-80 years with pathologically confirmed gastric adenocarcinoma scheduled for radical gastrectomy with lymph node dissection via laparoscopic or robotic approaches were eligible for inclusion 14 .Exclusion criteria comprised the presence of other malignancies, distant metastasis, an American Society of Anesthesiologists physical status score of 4 or 5, and conditions affecting intestinal motility such as prior bowel obstruction, major abdominal surgery, or uncontrolled diabetes mellitus 15,16 .Dropout criteria included patients undergoing additional bowel resection, extensive adhesiolysis, or conversion to laparotomy during surgery 6,8 .Additionally, patients allergic to mosapride or unable to consume oral medication were also designated for dropout.

Treatment and assessments
Participants were randomly assigned to either the control or experimental group by an independent clinical research coordinator not involved in surgery or postoperative care.Both patients and treating physicians remained unaware of the group assignment.The experimental group received 5.29 mg of mosapride thrice daily on postoperative days 1-5, whereas those in the control group received placebo pills (Placebo Pharmaceutical Co., Otsu city, Japan) following the same schedule.
During surgery, radiopaque markers within a capsule were placed at the bowel anastomosis site.Bowel transit time was measured by counting the visible radiopaque markers on plain radiographic images of the stomach, small bowel, or colon taken on postoperative days 1, 3, and 5 (Fig. 1) 17 .Laboratory examinations, including white blood cell (WBC) count, neutrophil count, and C-reactive protein levels, were conducted on the same day to assess inflammatory responses.Postoperative complications were classified according to the Clavien-Dindo classification 18 .
All patients adhered to the ERAS guidelines, encompassing anesthetic management, near-zero fluid balance, minimal opioid usage, avoidance of nasogastric tube insertion, early enteral nutrition, and prompt mobilization 12,13 .Epidural anesthesia was not administered during the study, and any additional analgesic administrations were diligently documented.
Patients followed a standardized diet protocol, including water sips on postoperative day 1, a liquid diet on postoperative day 2, and a soft diet on postoperative day 3, with possible delays based on individual tolerance levels.Food intake was assessed by evaluating the proportion of meals consumed.Daily abdominal discomfort was assessed until postoperative day 5 using a questionnaire based on the numerical rating scale, with scores ranging from 1 (very comfortable) to 5 (very uncomfortable).
The primary endpoint was the bowel transit time, assessed by counting radiopaque markers in the colon on postoperative day 3. Secondary endpoints included food intake amount, severity of abdominal discomfort, time to first flatus/defecation, and levels of inflammatory markers.

Statistical analysis
With a 10% dropout rate and 1:1 randomization, we aimed for 80% power with a two-sided significance level of 5%.On prior research, mosapride brought 1.4 times improvement in first defacation time.Therefore, we hypothesized at least a 1.3-fold improvement of bowel movement, assessed by the number of radiopaque markers passing into the colon in the experimental group compared to the control group 11 .Thus, a minimum of 52 patients per group was required.www.nature.com/scientificreports/Categorical variables are presented as numbers and proportions, and continuous variables as mean ± standard deviation.Categorical variables were analyzed using the chi-squared or Fisher's exact test, whereas the Kruskal-Wallis test was employed for ordinal variables.Continuous variables were assessed using Student's t-test.Repeated-measures ANOVA was used to comprehensively compare the differences between the two groups over time.Statistical significance was set at P < 0.05.All statistical analyses were conducted using SPSS software version 22 (IBM Corp., Armonk, NY, USA).

Patient characteristics
In total, planned 104 patients were enrolled between July 2020 and March 2021.Among them, 51 and 53 patients were allocated to the experimental and control groups, respectively.Three patients in the control group and two in the experimental group dropped out (Fig. 2).
Baseline characteristics such as age, medical history, type of operation, blood loss during the surgery, and operation time were well balanced between the two groups.However, the experimental group had a slightly higher proportion of women compared with the control group, although this difference was not statistically significant (54.9% vs. 35.4%;P = 0.052; Table 1).

Motility evaluation
No hazardous surgical events occurred during the insertion of radio-opaque markers.However, radio-opaque marker insertion was missed in seven patients during surgery: three patients in the placebo group and four patients in the experimental group.The analysis of the number of radiopaque markers was conducted only on patients who did not miss radiopaque marker insertion in each group, 45 patients in the control group, 47 patients in the experimental group.
On postoperative day 3, the average numbers of radiopaque markers detected in the colon were 14.0 ± 7.71 and 13.30 ± 7.50 in the control and experimental groups, respectively.We observed no statistically significant differences between the groups (P = 0.659; Table 2).
On postoperative day 5, the average numbers of markers detected in the colon were 17.89 ± 5.69 and 18.91 ± 3.28 in the control and experimental groups, respectively; however, this difference was not statistically significant (P = 0.29).After conducting subgroup analysis using stratification based on the anastomosis type, no statistically significant difference was observed (Table 3).
The levels of abdominal discomfort reported by the patients were similar in both groups.The average numeric rating scores of the questionnaire were 1.84 ± 1.04 and 1.77 ± 0.89 in the control and experimental groups, respectively (P = 0.837).
We observed no significant difference in the proportion of food intake between the two groups.On postoperative day 5, the average proportions of food intake were 63.09% ± 24.35% and 66.57% ± 21.97% in the control and experimental groups, respectively (P = 0.458).The times to the first flatus and defecation were similar between the two groups.
When analyzing the difference between the two groups over time using RM-ANOVA, the P-value did not indicate a significant difference on all variables associated with bowel motility (Fig. 3).

Postoperative outcomes
We observed no significant differences in the rate or severity of postoperative complications between the two groups.The length of hospital stays in both groups were similar (Table 4).No complications related to placebo or mosapride treatment, including allergic reactions or impaired liver function, were reported.Of the 101 enrolled patients, 27 experienced grade I complications, and 36 experienced grade II complications.Two patients were excluded owing to intolerance to oral medications.In the experimental group, one patient required reoperation owing to obstructive symptoms and the presence of malignant cells at the surgical margin.In the control group, one patient dropped out because of delayed gastric emptying.None of the patients experienced severe complications, such as anastomotic leakage or sepsis.
Finally, we observed no significant differences in the results of the laboratory examinations for assessing inflammation between the two groups (Table 4).

Discussion
In our study, we observed that mosapride citrate did not promote bowel motility in patients who had undergone minimally invasive gastrectomy performed in accordance with the ERAS protocol.
The ERAS protocol for patients undergoing gastrectomy includes the use of a laparoscopic approach, early resumption of postoperative oral nutrition, and minimal opioid use.However, motility-enhancing medication is only weakly recommended in the ERAS protocol for gastrectomy and its use has a very low evidence level 2 .Many prokinetic medications are associated with the 5-HT receptors.Mosapride citrate is a 5-HT 4 receptor agonist that increases the release of acetylcholine from excitatory neurons in the stomach and duodenum 19 .However, its propulsive effect on the small intestine and colon has remained unclear in previous studies 7,20 .
Patients who undergo laparoscopic colectomy can benefit from mosapride citrate, such as experiencing a shorter defecation period, reduced incidence of ileus, and shorter hospital stays 11,21,22 .In contrast, we did not observe a positive effect of mosapride on the postoperative recovery of bowel movements.The reasons for this negative observation may be as follows.First, unlike patients who have undergone colectomy, those who have undergone distal or total gastrectomy do not retain the gastric antrum.As the gastric antrum is the main target of mosapride, patients without the gastric antrum may experience reduced effects of mosapride.We anticipate that mosapride administration in patients undergoing pylorus-preserving gastrectomy or proximal gastrectomy, in which the gastric antrum is not removed during surgery, could lead to more significant effects.Second, mosapride is not only a 5-HT 4 receptor agonist but also a 5-HT 3 receptor antagonist 23 .Antagonists of 5-HT 3 receptors, such as ondansetron and alosetron, are used as antiemetic or antidiarrheal drugs.Ondansetron also slows colonic transit and inhibits the colonic motor response to meals 24,25 .Therefore, an antagonistic effect on 5-HT 3 receptors may be the pharmacological reason for the limited promotion of colonic motility by mosapride in the enrolled patients.Lastly, surgery inherently exerts a more direct and powerful influence on the bowel, leading to delayed and subdued effect of the drug in the context of surgery compared to that of medical conditions.In medical conditions such as diabetes or Parkinson's disease, mosapride effectively addresses constipation and decreased bowel motility.Patients with these conditions often exhibit an initial 5-HT system hypofunction in the gastrointestinal system.When administered, mosapride delivers an immediate and more pronounced impact by replacing 5-HT 26,27 .However, physical manipulation or thermal injury during surgery can affect the myenteric plexus of the gastrointestinal tract.The recovery and regeneration of neurons generally take approximately 10-14 days, as long as up to 6 weeks [28][29][30] .Postoperatively, 5 days may not be sufficient for neuronal recovery, leading to an unnoticed effect of the medication.Despite the lack of positive outcomes, to our knowledge, this is the first randomized, placebo-controlled study conducted to assess the efficacy of mosapride in patients undergoing minimally invasive gastrectomy.Additionally, the randomized, prospective trial design minimizes bias.However, the fact that it was conducted at a single center and the population was limited to Asians are limitations of this study.
Postoperative recovery of bowel motility is achieved starting from the small intestine followed by the stomach to the colon 31 .The recovery of colon motility may play a crucial role in reducing abdominal discomfort and promoting gas passage.Therefore, we assumed that prokinetic medications, which mainly act on the colon, may be more effective than mosapride, which acts on the stomach and duodenum.Further research on such agents might be required to identify intestinal recovery following gastrectomy.
In conclusion, mosapride citrate does not improve the recovery of intestinal motility following minimally invasive gastrectomy in patients with gastric cancer.Therefore, the routine postoperative use of mosapride citrate is not recommended in patients who have undergone minimally invasive gastrectomy.

Figure 1 .
Figure 1.Representative radiographic image of radiopaque markers observed in the colon.(Black arrow).

Figure 2 .
Figure 2. Flow chart of patient selection.

Figure 3 .
Figure 3. Clinical outcomes of two groups over time.Number of markers in (a) small bowel and (b) colon.(c) Abdominal discomfort score in numerical rating scale.(d) Proportion of food intake.Level of (e) CRP and (f) WBC count.*P-values compared the difference between two groups with RM-ANOVA.POD postoperative day; NRS numerical rating scale; CRP C-reactive Protein; WBC white blood cell.

Table 1 .
Patient characteristics.ASA American Society of Anesthesiologists physical status score, BMI Body mass index, B-I Billroth I, B-II Billroth II, STG R-Y Subtotal gastrectomy Roux-en Y, TG R-Y Total gastrectomy Roux-en Y.

Table 2 .
Clinical outcome associated with the gastrointestinal motility.POD postoperative day.

Table 3 .
Number of radiopaque markers in colon according to anastomosis type.POD postoperative day, B-I Billroth I, B-II Billroth II, STG R-Y Subtotal gastrectomy Roux-en Y, TG R-Y Total gastrectomy Roux-en Y.

Table 4 .
Laboratory Findings and Postoperative Course.POD postoperative day, CRP C-reactive Protein, WBC white blood cell.